1. Field of the Invention
The present invention relates to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin monohydrochloride trihydrate (irinotecan hydrochloride). More particularly, it relates to newly discovered crystalline forms having increased ease of filtering over previously produced irinotecan hydrochloride, to processes for producing these new crystalline forms, to pharmaceutical compositions containing the new forms, and methods of treating metastatic carcinoma of the colon or rectum using these new forms
2. Description of the Related Art
7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin monohydrochloride trihydrate having the molecular structure:
and formula C33H38N4O6.HCl.3H2O and a molecular weight of 677.19 is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, and alkaloid extract from plants such as Camptotheca acuminata. Irinotecan hydrochloride is approved by the Food and Drug Administration as a component of first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. It is also approved for treating patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. Physicians' Desk Reference, 59th ed., 2005. Irinotecan hydrochloride is commercially available in injection form under the trade name Camptosar®.
The present invention relates to novel solid state crystalline forms of irinotecan hydrochloride.
U.S. Pat. No. 4,604,463 discloses various processes for preparing global irinotecan and irinotecan hydrochloride. The '463 patent is incorporated by reference in its entirety and, specifically, for its teachings regarding the synthesis of irinotecan and irinotecan hydrochloride from commercially available and readily accessible starting materials.
In Example 19 of the '463 patent, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin was formed by suspending 10-Chlorocarbonyloxy-7-ethylcamptothecin in dry dioxane. 4-piperidinopiperidine was added to this suspension. The mixture was stirred until the starting materials were consumed. The solvent was then removed by distillation under reduced pressure and the residue was subjected to separation and purification by the aid of column chromatography on silica gel whereby 7-ethyl-10-[4(1-piperidino)- 1-piperidino]carbonyloxycamptothecin was obtained.
In Example 28 of the '463 patent, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin was formed by dissolving 7-ethyl-10-hydroxycamptothecin and 1-chlorocarbonyl-4-piperidinopiperidine in anhydrous pyridine, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in CHCl3. The solution was washed successively with a 7% aqueous solution of NaHCO3, a saturated aqueous solution NaCl, and the CHCl3 layer was dried with MgSO4, filtered, and evaporated in vacuo. The residual material was decolorized by passing it through a short silica gel column whereby 7-ethyl-10-[4(1-piperidino)-1piperidino]carbonyloxycamptothecin was obtained as a pale yellow mass, which was recrystallized from ethanol to give colorless needles.
In Example 37 of the '463 patent, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin hydrochloride was formed by adding 1/10N HCl to an ice-cooled suspension of 7-ethyl-10-[1-(4-piperidino)piperidino]carbonyloxycamptothecin in distilled water. The suspension was stirred vigorously for 5 minutes under cooling in an ice bath. The solution was passed through a filter (0.22 μm, SLGS 025 OS) and the filtrate was lyophilized overnight whereby 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin hydrochloride was obtained as a pale yellow amorphous solid.
We have now discovered and characterized novel crystalline forms of irinotecan hydrochloride that are more easily handled during the manufacturing process than previously known forms of irinotecan hydrochloride.
There is a need for new crystalline forms of irinotecan hydrochloride. The discovery of new crystalline forms of a pharmaceutical compound provides an improved manner of processing and producing a pharmaceutical product containing irinotecan hydrochloride. New crystalline forms increase the possibilities available to a scientist involved in the formulation of pharmaceutical products thereby allowing for the formulation of new and improved pharmaceutical compositions that would otherwise be unattainable, but for the invention of the new crystalline forms.